Development of an α-synuclein positron emission tomography tracer for imaging synucleinopathies.

Synucleinopathies are characterized by the accumulation of α-synuclein (α-Syn) aggregates in the brain. Positron emission tomography (PET) imaging of synucleinopathies requires radiopharmaceuticals that selectively bind α-Syn deposits. We report the identification of a brain permeable and rapid washout PET tracer [18F]-F0502B, which shows high binding affinity for α-Syn, but not for Aß or Tau fibrils, and preferential binding to α-Syn aggregates in the brain sections. Employing several cycles of counter screenings with in vitro fibrils, intraneuronal aggregates, and neurodegenerative disease brain sections from several mice models and human subjects, [18F]-F0502B images α-Syn deposits in the brains of mouse and non-human primate PD models. We further determined the atomic structure of the α-Syn fibril-F0502B complex by cryo-EM and revealed parallel diagonal stacking of F0502B on the fibril surface through an intense noncovalent bonding network via inter-ligand interactions. Therefore, [18F]-F0502B is a promising lead compound for imaging aggregated α-Syn in synucleinopathies.

FSH blockade improves cognition in mice with Alzheimer's disease.

Alzheimer's disease has a higher incidence in older women, with a spike in cognitive decline that tracks with visceral adiposity, dysregulated energy homeostasis and bone loss during the menopausal transition1,2. Inhibiting the action of follicle-stimulating hormone (FSH) reduces body fat, enhances thermogenesis, increases bone mass and lowers serum cholesterol in mice3-7. Here we show that FSH acts directly on hippocampal and cortical neurons to accelerate amyloid-ß and Tau deposition and impair cognition in mice displaying features of Alzheimer's disease. Blocking FSH action in these mice abrogates the Alzheimer's disease-like phenotype by inhibiting the neuronal C/EBPß-δ-secretase pathway. These data not only suggest a causal role for rising serum FSH levels in the exaggerated Alzheimer's disease pathophysiology during menopause, but also reveal an opportunity for treating Alzheimer's disease, obesity, osteoporosis and dyslipidaemia with a single FSH-blocking agent.

RNF20 contributes to epigenetic immunosuppression through CDK9-dependent LSD1 stabilization.

Cyclin-dependent kinase 9 (CDK9) plays a critical role in transcription initiation and is essential for maintaining gene silencing at heterochromatic loci. Inhibition of CDK9 increases sensitivity to immunotherapy, but the underlying mechanism remains unclear. We now report that RNF20 stabilizes LSD1 via K29-mediated ubiquitination, which is dependent on CDK9-mediated phosphorylation. This CDK9- and RNF20-dependent LSD1 stabilization is necessary for the demethylation of histone H3K4, then subsequent repression of endogenous retrovirus, and an interferon response, leading to epigenetic immunosuppression. Moreover, we found that loss of RNF20 sensitizes cancer cells to the immune checkpoint inhibitor anti-PD-1 in vivo and that this effect can be rescued by the expression of ectopic LSD1. Our findings are supported by the observation that RNF20 levels correlate with LSD1 levels in human breast cancer specimens. This study sheds light on the role of RNF20 in CDK9-dependent LSD1 stabilization, which is crucial for epigenetic silencing and immunosuppression. Our findings explore the potential importance of targeting the CDK9-RNF20-LSD1 axis in the development of new cancer therapies.

Ibrutinib and venetoclax as primary therapy in symptomatic, treatment-naïve Waldenström macroglobulinemia.

ABSTRACT: Concurrent Bruton tyrosine kinase and BCL2 inhibition has not yet been investigated in Waldenström macroglobulinemia (WM). We performed an investigator-initiated trial of ibrutinib and venetoclax in symptomatic treatment-naïve patients with MYD88-mutated WM. Patients received ibrutinib 420 mg once daily (cycle 1), followed by a ramp-up of venetoclax to 400 mg daily (cycle 2). The combination was then administered for 22 additional 4-week cycles. The attainment of very good partial response (VGPR) was the primary end point. Forty-five patients were enrolled in this study. The median baseline characteristics were as follows: age 67 years, serum IgM 43 g/L, and hemoglobin 102 g/L. Seventeen patients (38%) carried CXCR4 mutations. Nineteen patients (42%) achieved VGPR. Grade 3 or higher adverse events included neutropenia (38%), mucositis (9%), and tumor lysis syndrome (7%). Atrial fibrillation occurred in 3 (9%), and ventricular arrhythmia in 4 (9%) patients that included 2 grade 5 events. With a median follow-up of 24.4 months, the 24-month progression-free survival (PFS) and overall survival (OS) rates were 76% and 96%, respectively, and were not impacted by CXCR4 mutations. The median time on therapy was 10.2 months, and the median time after the end of therapy (EOT) was 13.3 months. Eleven of the 12 progression events occurred after EOT, and the 12-month PFS rates after EOT were 79%; 93% if VGPR was attained, and 69% for other patients (P = .12). Ibrutinib and venetoclax induced high VGPR rates and durable responses after EOT, although they were associated with a higher-than-expected rate of ventricular arrhythmia in patients with WM, leading to early study treatment termination. This trial was registered at www.clinicaltrials.gov as #NCT04273139.

A peptidomimetic modulator of the CaV2.2 N-type calcium channel for chronic pain.

Transmembrane Cav2.2 (N-type) voltage-gated calcium channels are genetically and pharmacologically validated, clinically relevant pain targets. Clinical block of Cav2.2 (e.g., with Prialt/Ziconotide) or indirect modulation [e.g., with gabapentinoids such as Gabapentin (GBP)] mitigates chronic pain but is encumbered by side effects and abuse liability. The cytosolic auxiliary subunit collapsin response mediator protein 2 (CRMP2) targets Cav2.2 to the sensory neuron membrane and regulates their function via an intrinsically disordered motif. A CRMP2-derived peptide (CBD3) uncouples the Cav2.2-CRMP2 interaction to inhibit calcium influx, transmitter release, and pain. We developed and applied a molecular dynamics approach to identify the A1R2 dipeptide in CBD3 as the anchoring Cav2.2 motif and designed pharmacophore models to screen 27 million compounds on the open-access server ZincPharmer. Of 200 curated hits, 77 compounds were assessed using depolarization-evoked calcium influx in rat dorsal root ganglion neurons. Nine small molecules were tested electrophysiologically, while one (CBD3063) was also evaluated biochemically and behaviorally. CBD3063 uncoupled Cav2.2 from CRMP2, reduced membrane Cav2.2 expression and Ca2+ currents, decreased neurotransmission, reduced fiber photometry-based calcium responses in response to mechanical stimulation, and reversed neuropathic and inflammatory pain across sexes in two different species without changes in sensory, sedative, depressive, and cognitive behaviors. CBD3063 is a selective, first-in-class, CRMP2-based peptidomimetic small molecule, which allosterically regulates Cav2.2 to achieve analgesia and pain relief without negative side effect profiles. In summary, CBD3063 could potentially be a more effective alternative to GBP for pain relief.

Gut inflammation triggers C/EBPß/δ-secretase-dependent gut-to-brain propagation of Aß and Tau fibrils in Alzheimer's disease.

Inflammation plays an important role in the pathogenesis of Alzheimer's disease (AD). Some evidence suggests that misfolded protein aggregates found in AD brains may have originated from the gut, but the mechanism underlying this phenomenon is not fully understood. C/EBPß/δ-secretase signaling in the colon was investigated in a 3xTg AD mouse model in an age-dependent manner. We applied chronic administration of 1% dextran sodium sulfate (DSS) to trigger gut leakage or colonic injection of Aß or Tau fibrils or AD patient brain lysates in 3xTg mice and combined it with excision/cutting of the gut-brain connecting vagus nerve (vagotomy), in order to explore the role of the gut-brain axis in the development of AD-like pathologies and to monitor C/EBPß/δ-secretase signaling under those conditions. We found that C/EBPß/δ-secretase signaling is temporally activated in the gut of AD patients and 3xTg mice, initiating formation of Aß and Tau fibrils that spread to the brain. DSS treatment promotes gut leakage and facilitates AD-like pathologies in both the gut and the brain of 3xTg mice in a C/EBPß/δ-secretase-dependent manner. Vagotomy selectively blunts this signaling, attenuates Aß and Tau pathologies, and restores learning and memory. Aß or Tau fibrils or AD patient brain lysates injected into the colon propagate from the gut into the brain via the vagus nerve, triggering AD pathology and cognitive dysfunction. The results indicate that inflammation activates C/EBPß/δ-secretase and initiates AD-associated pathologies in the gut, which are subsequently transmitted to the brain via the vagus nerve.

Tumor microenvironment metabolites directing T cell differentiation and function.

Metabolic reprogramming of cancer cells creates a unique tumor microenvironment (TME) characterized by the limited availability of nutrients, which subsequently affects the metabolism, differentiation, and function of tumor-infiltrating T lymphocytes (TILs). TILs can also be inhibited by tumor-derived metabolic waste products and low oxygen. Therefore, a thorough understanding of how such unique metabolites influence mammalian T cell differentiation and function can inform novel anticancer therapeutic approaches. Here, we highlight the importance of these metabolites in modulating various T cell subsets within the TME, dissecting how these changes might alter clinical outcomes. We explore potential TME metabolic determinants that might constitute candidate targets for cancer immunotherapies, ideally leading to future strategies for reprogramming tumor metabolism to potentiate anticancer T cell functions.

Predicting brain age using partition modeling strategy and atlas-based attentional enhancement in the Chinese population.

As a biomarker of human brain health during development, brain age is estimated based on subtle differences in brain structure from those under typical developmental. Magnetic resonance imaging (MRI) is a routine diagnostic method in neuroimaging. Brain age prediction based on MRI has been widely studied. However, few studies based on Chinese population have been reported. This study aimed to construct a brain age predictive model for the Chinese population across its lifespan. We developed a partition prediction method based on transfer learning and atlas attention enhancement. The participants were separated into four age groups, and a deep learning model was trained for each group to identify the brain regions most critical for brain age prediction. The Atlas attention-enhancement method was also used to help the models focus only on critical brain regions. The proposed method was validated using 354 participants from domestic datasets. For prediction performance in the testing sets, the mean absolute error was 2.218 ± 1.801 years, and the Pearson correlation coefficient (r) was 0.969, exceeding previous results for wide-range brain age prediction. In conclusion, the proposed method could provide brain age estimation to assist in assessing the status of brain health.

Delta-Secretase Phosphorylation by SRPK2 Enhances Its Enzymatic Activity, Provoking Pathogenesis in Alzheimer's Disease.

Delta-secretase, a lysosomal asparagine endopeptidase (AEP), simultaneously cleaves both APP and tau, controlling the onset of pathogenesis of Alzheimer's disease (AD). However, how this protease is post-translationally regulated remains unclear. Here we report that serine-arginine protein kinase 2 (SRPK2) phosphorylates delta-secretase and enhances its enzymatic activity. SRPK2 phosphorylates serine 226 on delta-secretase and accelerates its autocatalytic cleavage, leading to its cytoplasmic translocation and escalated enzymatic activities. Delta-secretase is highly phosphorylated in human AD brains, tightly correlated with SRPK2 activity. Overexpression of a phosphorylation mimetic (S226D) in young 3xTg mice strongly promotes APP and tau fragmentation and facilitates amyloid plaque deposits and neurofibrillary tangle (NFT) formation, resulting in cognitive impairment. Conversely, viral injection of the non-phosphorylatable mutant (S226A) into 5XFAD mice decreases APP and tau proteolytic cleavage, attenuates AD pathologies, and reverses cognitive defects. Our findings support that delta-secretase phosphorylation by SRPK2 plays a critical role in aggravating AD pathogenesis.

Atomic Ordering Engineering of Precious Metal Alloys in Liquid Phase Synthesis.

Atomic ordering of noble metal alloys is an effective strategy for improving catalytic performance, yet the low-temperature synthesis of ordered alloys still faces significant challenges. The low-temperature liquid phase method has enormous potential for the synthesis of alloys; however, the atomic ordering mechanism of this process has not been thoroughly studied. Herein, we investigate the mechanism of the influence of metal precursors, reducing agents, solvents, and mixing modes of reactant regulating strategies on precious metal alloy ordering using this method. These regulating strategies are designed to change the coordination structure of metal complexes, affect the reduction potential of metals, and thus change the reduction order of metals and their arrangement in the alloy products. Notably, the reduction potential differences between metal complexes can be used to predict the ordering of the synthetic products (Pd-Cu, Pd-Cd, Pd-Sn, Pd-Pb, and Pt-Sn). This work provides an excellent platform for investigating atomic arrangement engineering.

Decreased Tiam1-mediated Rac1 activation is responsible for impaired directional persistence of chondrocyte migration in microtia.

The human auricle has a complex structure, and microtia is a congenital malformation characterized by decreased size and loss of elaborate structure in the affected ear with a high incidence. Our previous studies suggest that inadequate cell migration is the primary cytological basis for the pathogenesis of microtia, however, the underlying mechanism is unclear. Here, we further demonstrate that microtia chondrocytes show a decreased directional persistence during cell migration. Directional persistence can define a leading edge associated with oriented movement, and any mistakes would affect cell function and tissue morphology. By the screening of motility-related genes and subsequent confirmations, active Rac1 (Rac1-GTP) is identified to be critical for the impaired directional persistence of microtia chondrocytes migration. Moreover, Rho guanine nucleotide exchange factors (GEFs) and Rho GTPase-activating proteins (GAPs) are detected, and overexpression of Tiam1 significantly upregulates the level of Rac1-GTP and improves directional migration in microtia chondrocytes. Consistently, decreased expression patterns of Tiam1 and active Rac1 are found in microtia mouse models, Bmp5se/J and Prkralear-3J/GrsrJ. Collectively, our results provide new insights into microtia development and therapeutic strategies of tissue engineering for microtia patients.

Cell aggregation activates small GTPase Rac1 and induces CD44 cleavage by maintaining lipid raft integrity.

Lipid rafts are highly ordered membrane domains that are enriched in cholesterol and glycosphingolipids and serve as major platforms for signal transduction. Cell detachment from the extracellular matrix (ECM) triggers lipid raft disruption and anoikis, which is a barrier for cancer cells to metastasize. Compared to single circulating tumor cells (CTCs), our recent studies have demonstrated that CD44-mediatd cell aggregation enhances the stemness, survival and metastatic ability of aggregated cells. Here, we investigated whether and how lipid rafts are involved in CD44-mediated cell aggregation. We found that cell detachment, which mimics the condition when tumor cells detach from the ECM to metastasize, induced lipid raft disruption in single cells, but lipid raft integrity was maintained in aggregated cells. We further found that lipid raft integrity in aggregated cells was required for Rac1 activation to prevent anoikis. In addition, CD44 and γ-secretase coexisted at lipid rafts in aggregated cells, which promoted CD44 cleavage and generated CD44 intracellular domain (CD44 ICD) to enhance stemness of aggregated cells. Consequently, lipid raft disruption inhibited Rac1 activation, CD44 ICD generation, and metastasis. Our findings reveal two new pathways regulated by CD44-mediated cell aggregation via maintaining lipid raft integrity. These findings also suggest that targeting cell aggregation-mediated pathways could be a novel therapeutic strategy to prevent CTC cluster-initiated metastasis.

Low FHL1 expression indicates a good prognosis and drug sensitivity in ovarian cancer.

Chemotherapy resistance is the main reason for the poor prognosis of ovarian cancer (OC). FHL1 is an important tumour regulator, but its relationship with the prognosis, drug resistance, and tumour microenvironment of OC is unknown. Immunohistochemistry was used to determine FHL1 expression in OC. Kaplan‒Meier plotter was used for survival analysis. The value of gene expression in predicting drug resistance was estimated using the area under the curve (AUC). Bivariate correlation was used to determine the coexpression of two genes. Functional cluster and pathway enrichment were used to uncover hidden signalling pathways. The relationship between gene levels and the tumour microenvironment was visualised through the ggstatsplot and pheatmap packages. The mRNA and protein levels of FHL1 were downregulated in 426 and 100 OC tissues, respectively. Low FHL1 expression was correlated with good progression-free survival (PFS), postprogression survival, and overall survival (OS) in 1815 OC patients, and was further confirmed to be associated with good OS by immunohistochemistry in 152 OC tissues. Furthermore, FHL1 was downregulated in drug-sensitive tissues, while its high expression predicted drug resistance (AUC > 0.65). Mechanistically, FHL1 was coexpressed with FLNC, CAV1, PPP1R12B, and FLNA at the mRNA and protein levels in 558 and 174 OC tissues, respectively, and their expression was downregulated in OC. Additionally, very strong coexpression of FHL1 with the four genes was identified in at least 23 different tumours. Low expression of the four genes was associated with good PFS, and the combination of FHL1 with the four genes provided better prognostic power. Meanwhile, the expression of all five genes was strongly and positively associated with the abundance of macrophages. Low FHL1 expression acts as a favourable factor in OC, probably via positive coexpression with FLNC, CAV1, PPP1R12B, and FLNA.

Epidemiological features and prognosis for primary gastrointestinal follicular lymphoma.

Primary gastrointestinal follicular lymphoma (PGI-FL) is a rare extra-nodal lymphoma. Its epidemiology and prognosis remain unclear. We performed a retrospective analysis of eligible patients with 1648 PGI-FL and 34 892 nodal FL (N-FL) in the Surveillance, Epidemiology and End Results (SEER) database. The age-adjusted average annual incidence of PGI-FL was 0.111/100000. The median overall survival (OS) for PGI-FL and N-FL patients was 207 and 165 months respectively. The 5-year diffuse large B-cell lymphoma (DLBCL) transformation rates were 2.1% and 2.6% respectively. Age, sex, grade, Ann Arbor stage, primary site and radiation were independent prognostic factors (p < 0.05). Nomograms were constructed to predict 1-, 5- and 10-year OS and disease-specific survival (DSS). The receiver operating characteristic curves and calibration plots showed the established nomograms had robust and accurate performance. Patients were classified into three risk groups according to nomogram score. In conclusion, the incidence of PGI-FL has increased over the past 40 years, and PGI-FL has a better prognosis and a lower DLBCL transformation rate than N-FL. The nomograms were developed and validated as an individualized tool to predict survival. Patients were divided into three risk groups to assist clinicians in identifying high-risk patients and choosing the optimal individualized treatments.

Long-term Risks of Cirrhosis and Hepatocellular Carcinoma Across Steatotic Liver Disease Subtypes.

INTRODUCTION: The prospective study aimed to investigate the long-term associated risks of cirrhosis and hepatocellular carcinoma (HCC) across various subtypes of steatotic liver disease (SLD). METHODS: We enrolled 332,175 adults who participated in a health screening program between 1997 and 2013. Participants were categorized into various subtypes, including metabolic dysfunction-associated SLD (MASLD), MASLD with excessive alcohol consumption (MetALD), and alcohol-related liver disease (ALD), based on ultrasonography findings, alcohol consumption patterns, and cardiometabolic risk factors. We used computerized data linkage with nationwide registries from 1997 to 2019 to ascertain the incidence of cirrhosis and HCC. RESULTS: After a median follow-up of 16 years, 4,458 cases of cirrhosis and 1,392 cases of HCC occurred in the entire cohort, resulting in an incidence rate of 86.1 and 26.8 per 100,000 person-years, respectively. The ALD group exhibited the highest incidence rate for cirrhosis and HCC, followed by MetALD, MASLD, and non-SLD groups. The multivariate adjusted hazard ratios for HCC were 1.92 (95% confidence interval [CI] 1.51-2.44), 2.91 (95% CI 2.11-4.03), and 2.59 (95% CI 1.93-3.48) for MASLD, MetALD, and ALD, respectively, when compared with non-SLD without cardiometabolic risk factors. The pattern of the associated risk of cirrhosis was similar to that of HCC (all P value <0.001). The associated risk of cirrhosis for ALD increased to 4.74 (95% CI 4.08-5.52) when using non-SLD without cardiometabolic risk factors as a reference. DISCUSSION: This study highlights elevated risks of cirrhosis and HCC across various subtypes of SLD compared with non-SLD, emphasizing the importance of behavioral modifications for early prevention.

Hsa_circ_0005397 promotes hepatocellular carcinoma progression through EIF4A3.

PURPOSE: The purpose of this study was to explore the expression and potential mechanism of hsa_circ_0005397 in hepatocellular carcinoma progression. METHODS: Quantitative reverse transcription-polymerase chain reaction(qRT-PCR) was used to measure the expression level of hsa_circ_0005397 and EIF4A3 from paired HCC tissues and cell lines. Western Blot (WB) and immunohistochemistry (IHC) were used to verify the protein level of EIF4A3. The specificity of primers was confirmed by agarose gel electrophoresis. Receiver Operating Characteristic (ROC) Curve was drawn to analyze diagnostic value. Actinomycin D and nuclear and cytoplasmic extraction assays were utilized to evaluate the characteristics of hsa_circ_0005397. Cell Counting kit-8 (CCK-8) and colony formation assays were performed to detect cell proliferation. Flow cytometry analysis was used to detect the cell cycle. Transwell assay was performed to determine migration and invasion ability. RNA-binding proteins (RBPs) of hsa_circ_0005397 in HCC were explored using bioinformatics websites. The relationship between hsa_circ_0005397 and Eukaryotic Translation Initiation Factor 4A3 (EIF4A3) was verified by RNA Binding Protein Immunoprecipitation (RIP) assays, correlation and rescue experiments. RESULTS: In this study, hsa_circ_0005397 was found to be significantly upregulated in HCC, and the good diagnostic sensitivity and specificity shown a potential diagnostic capability. Upregulated expression of hsa_circ_0005397 was significantly related to tumor size and stage. Hsa_circ_0005397 was circular structure which more stable than liner mRNA, and mostly distributed in the cytoplasm. Upregulation of hsa_circ_0005397 generally resulted in stronger proliferative ability, clonality, and metastatic potency of HCC cells; its downregulation yielded the opposite results. EIF4A3 is an RNA-binding protein of hsa_circ_0005397, which overexpressed in paired HCC tissues and cell lines. In addition, expression of hsa_circ_0005397 decreased equally when EIF4A3 was depleted. RIP assays and correlation assay estimated that EIF4A3 could interacted with hsa_circ_0005397. Knockdown of EIF4A3 could reverse hsa_circ_0005397 function in HCC progression. CONCLUSIONS: Hsa_circ_0005397 promotes progression of hepatocellular carcinoma through EIF4A3. These research findings may provide novel clinical value for hepatocellular carcinoma.

Metabolic pathway-based subtyping reveals distinct microenvironmental states associated with diffuse large B-cell lymphoma outcomes.

Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease that requires personalized clinical treatment. Assigning patients to different risk categories and cytogenetic abnormality and genetic mutation groups has been widely applied for prognostic stratification of DLBCL. Increasing evidence has demonstrated that dysregulated metabolic processes contribute to the initiation and progression of DLBCL. Metabolic competition within the tumor microenvironment is also known to influence immune cell metabolism. However, metabolism- and immune-related stratification has not been established. Here, 1660 genes involved in 84 metabolic pathways were selected and tested to establish metabolic clusters (MECs) of DLBCL. MECs established based on independent lymphoma datasets distinguished different survival outcomes. The CIBERSORT algorithm and EcoTyper were applied to quantify the relative abundance of immune cell types and identify variation in cell states for 13 lineages comprising the tumor micro environment among different MECs, respectively. Functional characterization showed that MECs were an indicator of the immune microenvironment and correlated with distinctive mutational characteristics and oncogenic signaling pathways. The novel immune-related MECs exhibited promising clinical prognostic value and potential for informing DLBCL treatment decisions.

Effect of Regional Brain Activity Following Repeat Transcranial Magnetic Stimulation in SCA3: A Secondary Analysis of a Randomized Clinical Trial.

Repetitive transcranial magnetic stimulation (rTMS), a noninvasive neuroregulatory technique used to treat neurodegenerative diseases, holds promise for spinocerebellar ataxia type 3 (SCA3) treatment, although its efficacy and mechanisms remain unclear. This study aims to observe the short-term impact of cerebellar rTMS on motor function in SCA3 patients and utilize resting-state functional magnetic resonance imaging (RS-fMRI) to assess potential therapeutic mechanisms. Twenty-two SCA3 patients were randomly assigned to receive actual rTMS (AC group, n = 11, three men and eight women; age 32-55 years) or sham rTMS (SH group, n = 11, three men and eight women; age 26-58 years). Both groups underwent cerebellar rTMS or sham rTMS daily for 15 days. The primary outcome measured was the ICARS scores and parameters for regional brain activity. Compared to baseline, ICARS scores decreased more significantly in the AC group than in the SH group after the 15-day intervention. Imaging indicators revealed increased Amplitude of Low Frequency Fluctuation (ALFF) values in the posterior cerebellar lobe and cerebellar tonsil following AC stimulation. This study suggests that rTMS enhances motor functions in SCA3 patients by modulating the excitability of specific brain regions and associated pathways, reinforcing the potential clinical utility of rTMS in SCA3 treatment. The Chinese Clinical Trial Registry identifier is ChiCTR1800020133.

Helicobacter hepaticus augmentation triggers Dopaminergic degeneration and motor disorders in mice with Parkinson's disease.

Gut dysbiosis contributes to Parkinson's disease (PD) pathogenesis. Gastrointestinal disturbances in PD patients, along with gut leakage and intestinal inflammation, take place long before motor disorders. However, it remains unknown what bacterial species in gut microbiomes play the key role in driving PD pathogenesis. Here we show that Helicobacter hepaticus (H. hepaticus), abundant in gut microbiota from rotenone-treated human α-Synuclein gene (SNCA) transgenic mice and PD patients, initiates α-Synuclein pathology and motor deficits in an AEP-dependent manner in SNCA mice. Chronic Dextran sodium sulfate (DSS) treatment, an inflammatory inducer in the gut, activates AEP (asparagine endopeptidase) that cleaves α-Synuclein N103 and triggers its aggregation, promoting inflammation in the gut and the brain and motor defects in SNCA mice. PD fecal microbiota transplant or live H. hepaticus administration into antibiotics cocktail (Abx)-pretreated SNCA mice induces α-Synuclein pathology, inflammation in the gut and brain, and motor dysfunctions, for which AEP is indispensable. Hence, Helicobacter hepaticus enriched in PD gut microbiomes may facilitate α-Synuclein pathologies and motor impairments via activating AEP.